With the exception of a few known vulnerabilities to a COVID-19 infection, such as age and co-morbidities, true mediators of critical cases of COVID-19 have remained elusive. Now, an international team has employed a multi-omics analysis combined with artificial intelligence in a young patient cohort where major co-morbidities were excluded at the onset. The study identified genetic patterns that may help explain why some young, healthy people still develop severe or life-threatening cases of COVID-19. By offering insight into a major unanswered question in the ongoing pandemic, the findings from a study of 72 patients could inform research into new diagnostic, prognostic, and therapeutic strategies for the disease.

This work was published in Science in the paper, “Identification of driver genes for critical forms of COVID-19 in a deeply phenotyped young patient cohort.”

Despite the enormous global toll that COVID-19 has wrought, many of the condition’s molecular drivers remain a mystery. For example, researchers are still studying why some patients develop lung failure and require ventilation and intensive care, while others show only mild or asymptomatic illness.

And, although the elderly and those with co-morbidities are more affected, critical cases can appear even in younger adults with no co-morbidities who are seemingly indistinguishable from their peers. To understand why, Raphael Carapito, PhD, associate faculty member in the Human Molecular Immunogenetics Group at the University of Strasbourg and colleagues used machine learning and multi-omics techniques to study 72 French patients under the age of 50 who were hospitalized with COVID-19 and had no known co-morbidities.

The researchers analyzed plasma samples from a cohort that included 47 “critical” (in the intensive care unit under mechanical ventilation) and 25 “noncritical” (in a noncritical care ward) patients with COVID-19 and 22 healthy individuals. The analyses included whole-genome sequencing, whole-blood RNA sequencing, plasma and blood mononuclear cells proteomics, cytokine profiling, and high-throughput immunophenotyping. Patients with critical COVID-19 were characterized by exacerbated inflammation, perturbed lymphoid and myeloid compartments, increased coagulation, and viral cell biology. The most prominent genetic signature linked with critical COVID-19 was higher expression of the metalloprotease ADAM9. This signature also appeared in a second group of 81 critical cases of COVID-19 and 73 recovered cases.

The team also found that silencing ADAM9 in human lung epithelial cells infected with SARS-CoV-2 slowed the replication of the virus, suggesting that the gene should be further studied as a potential therapeutic target. The authors wrote that a repurposing strategy using ADAM9-blocking antibodies for the treatment of critical COVID-19 patients “could therefore be envisioned.” Alternatively, they noted, other therapeutic agents to reduce the ADAM9 concentration or activity could be pursued.

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